First studies on the interactions of the C-terminal cystatin C fragment 85–94 with Cu(II) ions

Abstract

The hypothesis connecting dyshomeostasis of selected metal ions in the brain with increased probability of the development of severe neurodegenerative diseases is gaining increasing attention. The mechanisms of metal toxicity can be studied using different methodologies. One of the approaches is based on peptides as mimetics of the metal binding sites in proteins. In our studies, we have focused on human cystatin C (hCC) as one of the proteins involved in neurodegeneration. Physiologically, it is an important inhibitor of cysteine proteases and modulator of many physiological and pathological states. Native hCC is present at particularly high concentrations in cerebrospinal fluid (CSF) and was shown to possess both neurodegenerative and neuroprotective propensities. We have studied the copper(II) binding to its C-terminal fragment containing two histidine residues as potential site(s) for metal coordination. Our data indicate that the hCC fragment is fully capable of effective metal binding. Moreover, two potential metal binding sites can be proposed for the studied ligand. At the physiological range of pH formation of two types of complexes was observed: with imidazole and one/two amide donors in the coordination sphere of the metal ion and the final species characterized by the 4N-type of coordination.